Lysosome-Sarcoplasmic Reticulum Junctions

100

Ca2؉ regulates a spectrum of cellular processes including many aspects of neuronal function. Ca 2؉ -sensitive events such as neurite extension and axonal guidance are driven by Ca 2؉ signals that are precisely organized in both time and space. These complex cues result from both Ca 2؉ influx across the plasma membrane and the mobilization of intracellular Ca 2؉ stores. In the present study, using rat cortical neurons, we have examined the effects of the novel intracellular Ca 2؉ -mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) on neurite length and cytosolic Ca 2؉ levels. We show that NAADP potentiates neurite extension in response to serum and nerve growth factor and stimulates increases in cytosolic Ca 2؉ from bafilomycin-sensitive Ca 2؉ stores. Simultaneous blockade of inositol trisphosphate and ryanodine receptors abolished the effects of NAADP on neurite length and reduced the magnitude of NAADP-mediated Ca 2؉ signals. This is the first report demonstrating functional NAADP receptors in a mammalian neuron. Interplay between NAADP receptors and more established intracellular Ca 2؉ channels may therefore play important signaling roles in the nervous system.

Section: Resultssupporting

confidence: 90%

Nicotinic Acid Adenine Dinucleotide Phosphate Potentiates Neurite Outgrowth

Brǎiloiu

Hoard

Filipeanu

et al. 2005

100

“…This method takes advantage of the irreversible binding of NAADP to its yet uncharacterized receptor (46). With this assay, an NAADP concentration of 4 M has been determined in activated sea urchin sperms (13) as well as an increase in cellular NAADP levels upon stimulation of pancreatic beta cells with glucose (10), upon stimulation of murine pancreatic acinar cells with cholecystokinin (11), and upon stimulation of arterial smooth muscle cells with endothelin-1 (12). In addition, basal cellular concentrations of NAADP in erythrocytes (16 nM), rat hepatocytes (4.5 nM), and Escherichia coli cells (2.5 nM) have been reported (14).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore NAADP-induced Ca 2ϩ release via RyR has been described for MIN6 cells (22), pancreatic acinar cells (23,24), and human T cells (25,26). Galione and co-workers (10,12,27,28) recently reported the release of Ca 2ϩ by NAADP from a lysosomal compartment. Thus, both a "one pool-one receptor" mechanism (NAADP directly activates RyR) and a "two-pool" mechanism (NAADP releases Ca 2ϩ from a lysosomal store, which than induces Ca 2ϩ release by RyR) may be used by different cell types (for a review, see Ref.…”

mentioning

confidence: 96%

“…Moreover because extracellular stimulation induces increases in intracellular NAADP levels, a second messenger function for NAADP has been proposed in a few experimental systems (for reviews, see Refs. 8 and 9), including murine pancreatic beta cells (10), murine pancreatic acinar cells (11), and arterial smooth muscle cells (12). However, the determination of NAADP is still difficult because the data published so far were obtained by a radioligand binding assay requiring sea urchin egg homogenates as well as 32 P-labeled NAADP (10 -14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Second Messenger Function of Nicotinic Acid Adenine Dinucleotide Phosphate Revealed by an Improved Enzymatic Cycling Assay

Gasser¹,

Bruhn²,

Guse

2006

102

140

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent activator of Ca 2؉ release from intracellular stores known today. Although recent reports have suggested an important function of NAADP in human T lymphocytes, direct evidence for receptor-induced formation of NAADP is yet missing in these cells. Thus, we developed a highly sensitive and specific enzyme assay capable of quantifying low fmol amounts of NAADP. In unstimulated T cells, the NAADP concentration amounted to 4.4 ؎ 1.6 nM (0.055 ؎ 0.028 pmol/mg of protein). Stimulation of the cells via the T cell receptor/CD3 complex resulted in biphasic elevation kinetics of cellular NAADP levels and was characterized by a bell-shaped concentration-response curve for NAADP. In contrast, the NAADP concentration was elevated neither upon activation of the ADPribose/TRPM2 channel Ca 2؉ signaling system nor by an increase of the intracellular Ca 2؉ concentration upon thapsigargin stimulation. T cell receptor/CD3 complex-mediated NAADP formation was dependent on the activity of tyrosine kinases because genistein completely blocked NAADP elevation. Thus, we propose a regulated formation of NAADP upon specific stimulation of the T cell receptor/CD3 complex, suggesting a function of NAADP as a Ca 2؉ -mobilizing second messenger during T cell activation.During a rise of the intracellular Ca 2ϩ concentration, Ca 2ϩ either enters the cell from the extracellular space or is released from intracellular stores. The latter process is regulated by an expanding group of intracellular messengers (1, 2) including D-myo-inositol 1,4,5-trisphosphate (InsP 3 ), 3 cyclic ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP). In addition, Ca 2ϩ itself co-modulates Ca 2ϩ release via both InsP 3 receptors and ryanodine receptors (RyR).Clapper et al. (3) reported a Ca 2ϩ releasing activity of a contamination in commercially available NADP preparations. Nearly a decade later, this contamination was identified as NAADP, which turned out to be the most potent Ca 2ϩ -mobilizing compound in sea urchin egg homogenates (4). NAADP is active in a variety of cells, ranging from plants to animals (for reviews, see Refs. 5-7). Interestingly the functional properties of NAADP-induced Ca 2ϩ release in sea urchin egg homogenates are different from the systems activated by InsP 3 or cADPR (4). Moreover because extracellular stimulation induces increases in intracellular NAADP levels, a second messenger function for NAADP has been proposed in a few experimental systems (for reviews, see Refs. 8 and 9), including murine pancreatic beta cells (10), murine pancreatic acinar cells (11), and arterial smooth muscle cells (12). However, the determination of NAADP is still difficult because the data published so far were obtained by a radioligand binding assay requiring sea urchin egg homogenates as well as 32 P-labeled NAADP (10 -14).The molecular identity of the NAADP receptor is still controversial. Although a specific receptor has been proposed in sea urchin eggs (4, 15,...

“…Using isolated cells or tissues, NAADP-induced Ca 2ϩ signaling has been implicated in the regulation of several physiological functions such as egg fertilization (12,13), T lymphocyte activation (14), muscle contraction (15), and neuronal differentiation (16). The role of NAADP in vivo, however is not known, although a recent study demonstrated that a newly described NAADP antagonist could prevent T cell motility in an animal model of multiple sclerosis (17).…”

mentioning

confidence: 99%

Acidic NAADP-sensitive Calcium Stores in the Endothelium

Brailoiu

Gurzu

Gào

et al. 2010

Self Cite

Accumulating evidence implicates nicotinic acid adenine dinucleotide phosphate (NAADP) in the control of Ca2؉ -dependent functions. Little, however, is known concerning its role in the vascular endothelium, a major regulator of blood pressure. Here, we show that NAADP acetoxymethyl ester (NAADP-AM), a cell-permeant NAADP analog, increases cytosolic Ca 2؉ concentration in aortic endothelial cells. We demonstrate that these signals and those evoked by acetylcholine are blocked by disrupting acidic organelles with bafilomycin A1. In contrast, Ca 2؉ signals in response to thrombin are only partially inhibited by bafilomycin A1 treatment, and those to ATP were insensitive, suggesting that recruitment of acidic stores is agonist-specific. We further show that NAADP-evoked Ca 2؉ signals hyperpolarize endothelial cells and generate NO. Additionally, we demonstrate that NAADP dilates aortic rings in an endothelium-and NO-dependent manner. Finally, we show that intravenous administration of NAADP-AM into anesthetized rats decreases mean arterial pressure. Our data extend the actions of NAADP to the endothelium both in vitro and in vivo, pointing to a previously unrecognized role for this messenger in controlling blood pressure.Nicotinic acid adenine dinucleotide phosphate (NAADP) 4 is a potent and widespread Ca 2ϩ -mobilizing messenger first described in sea urchin eggs (1, 2). Although its mechanism of action is subject to debate, much evidence indicates that NAADP mobilizes Ca 2ϩ from acidic, lysosome-like organelles (3) through activation of novel Ca 2ϩ -permeable channels (1, 4). These channels have recently been identified as members of the two-pore channel family (5-9). Importantly, mobilization of so-called "acidic Ca 2ϩ stores" (10) by NAADP is often linked to mobilization of the well established endoplasmic reticulum Ca 2ϩ stores through the process of Ca 2ϩ -induced Ca 2ϩ release (11). NAADP is thus thought to act as trigger during agonistevoked Ca 2ϩ signaling (2). The functional positioning of NAADP-sensitive Ca 2ϩ stores upstream of those targeted by the messengers, inositol 1,4,5-trisphosphate (IP 3 ) and cyclic ADP-ribose, raises the possibility that agonist-evoked Ca 2ϩ signals previously ascribed to endoplasmic reticulum Ca 2ϩ release might also involve NAADP and acidic organelles.Using isolated cells or tissues, NAADP-induced Ca 2ϩ signaling has been implicated in the regulation of several physiological functions such as egg fertilization (12, 13), T lymphocyte activation (14), muscle contraction (15), and neuronal differentiation (16). The role of NAADP in vivo, however is not known, although a recent study demonstrated that a newly described NAADP antagonist could prevent T cell motility in an animal model of multiple sclerosis (17).In the cardiovascular system, a role for NAADP has been demonstrated in agonist-evoked Ca 2ϩ signaling in pulmonary (15, 18) and coronary arteries (19,20), cardiac myocytes (21), and the renal microcirculation (22). Direct measurements of NAADP have confirmed its messenge...